Schizophrenia is a severe disorder characterized by psychotic symptoms such as delusions and hallucinations and/or debilitating behavioral symptoms. Schizophrenia afflicts approximately one percent of the population worldwide, making this one of the most widespread diseases known. Despite the severity and prevalence of the disease, the complexity of schizophrenia has hindered efforts to understand its biochemical basis. Recent evidence suggests that DNA expansion may be associated with the disease in a subset of familial cases of schizophrenia in which the disease families display intergenerational "anticipation." Anticipation is characterized by progressive severity and earlier onset of disease in successive generations and is caused by expansion of simple trinucleotide repeats. It is our hypothesis that if anticipation occurs in a subset of schizophrenics, then the disrupted gene or genes must contain an expansion of a trinucleotide repeat region. Based on this hypothesis, we have developed a novel and powerful method to directly clone gene fragments containing trinucleotide repeats from schizophrenia patients in families that display anticipation. We have patient samples and access to medical records from one of the largest group of schizophrenics assessed for anticipation; we will apply our method to this population. Briefly, novel bead-probes will select for long trinucleotide repeat regions and their associated flanking sequence. The flanking sequence is part of the disrupted gene. The sequence of the flanking regions will be considered "candidates" from expansion and disease which will be verified by screening two large schizophrenia populations. One is the 16 family group comprising schizophrenia patients associated with anticipation phenotype. The other, larger group is a bank of 750 unrelated schizophrenia patients and 4000 controls. The frequency, distribution and genotype to phenotype analysis of expanded and polymorphic alleles will be assessed using a combination of both data banks. Finally, we will use the flanking sequence as a probe to complete the cloning of any novel genes associated with disease. The clear link between anticipation and expansion has provided new information that we have exploited to clone schizophrenia-related genes. Cloning of at least one gene will likely provide invaluable information towards understanding both the etiology and the biochemical basis for the disease.